Mesenchymal Contribution to Recruitment, Infiltration, and Positioning of Leukocytes in Human Melanoma Tissues

• Published in: Journal of investigative dermatology Vol. 133; no. 9; pp. 2255 - 2264
• Main Authors: Samaniego, Rafael, Estecha, Ana, Relloso, Miguel, Longo, Natividad, Escat, José L., Longo-Imedio, Isabel, Avilés, José A., del Pozo, Miguel Á., Puig-Kröger, Amaya, Sánchez-Mateos, Paloma
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2013; Elsevier Limited
• Subjects: Animals; Biopsy; CD90 antigen; Cell Communication - immunology; Cell Movement - immunology; Chemokine CCL2 - immunology; Humans; Leukocytes - immunology; Leukocytes - pathology; Melanoma - blood supply; Melanoma - immunology; Melanoma - secondary; Mesoderm - immunology; Mesoderm - pathology; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Transplantation; Receptors, CCR2 - immunology; Skin Neoplasms - blood supply; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Stromal Cells - immunology; Stromal Cells - pathology; Tumor Microenvironment - immunology
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2013.88

To understand factors that regulate leukocyte entry and positioning within human melanoma tissues, we performed a multiparametric quantitative analysis of two separated regions: the intratumoral area and the peritumoral stroma. Using two mesenchymal markers, fibroblast activation protein (FAP) and CD90, we identified three subsets of mesenchymal cells (MCs): (i) intratumoral FAP+CD90low/− MC, (ii) peritumoral FAP+CD90+ MC, and (iii) FAP−CD90+ perivascular MC. We characterized CD90+ MCs, which showed a stable CCL2-secretory phenotype when long-term expanded ex vivo, and heavily surrounded peritumoral Duffy antigen receptor for chemokine+ (DARC) postcapillary venules, supporting a role for these vessels in peritumoral inflammatory leukocyte recruitment. Conversely, the intratumoral area was variably invaded by FAP+CD90low/− MCs that colocalized with a distinct extracellular matrix (ECM) network. A positive correlation was observed between intratumoral stromal cell/ECM networks and leukocyte infiltration among tumor cells (TCs), as well as in a stroma-dependent xenograft tumor model. Adoptively transferred T lymphocytes preferentially infiltrated tumors composed of TC+MC, compared with TCs only. Altogether, our results suggest that a variety of MCs contribute to regulate different steps of leukocyte tumor infiltration, that is, CD90+ cells surrounding peritumoral vessels secrete CCL2 to recruit CCR2+ leukocytes at the tumor periphery, whereas intratumoral FAP+ cells organize a stromal scaffold that contact guide further invasion among densely packed tumor cells.